WO2016151451A1 - Procédé de préparation de chlorhydrate de lorcasérine - Google Patents

Procédé de préparation de chlorhydrate de lorcasérine Download PDF

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Publication number
WO2016151451A1
WO2016151451A1 PCT/IB2016/051535 IB2016051535W WO2016151451A1 WO 2016151451 A1 WO2016151451 A1 WO 2016151451A1 IB 2016051535 W IB2016051535 W IB 2016051535W WO 2016151451 A1 WO2016151451 A1 WO 2016151451A1
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WO
WIPO (PCT)
Prior art keywords
acetate
lorcaserin
methyl
formula
solvent
Prior art date
Application number
PCT/IB2016/051535
Other languages
English (en)
Inventor
Sukumar Nandi
Akkina NARESH
Syam Prasad Reddy ANNAREDDY
Gona BALA NARASIMHA REDDY
Meenakshi Sunderam SIVAKUMARAN
Original Assignee
Aurobindo Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Priority to EP16767827.5A priority Critical patent/EP3273967A4/fr
Priority to US15/741,722 priority patent/US10308611B2/en
Publication of WO2016151451A1 publication Critical patent/WO2016151451A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a process for the preparation of Lorcaserin hydrochloride hemih drate of Formula la,
  • Lorcaserin of Formula (I) is chemically known as (R)-8-chIorol-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine hydrochloride.
  • Lorcaserin hydrochloride of Formula (I) is an agonist of the 5-HT 2C receptor and shows effectiveness at reducing obesity in animal models and humans. Further, 5-HT 2C receptor is recognized as a well-accepted receptor target for the treatment of obesity, psychiatric, and other disorders.
  • Lorcaserin hydrochloride of Formula (I) is approved as anti-obesity agent and is marketed under the brand name Belvi in USA.
  • US patent No. 6,953,787 discloses Lorcaserin or a pharmaceutically acceptable salt, solvate or hydrate thereof. US '787 also discloses the process for the preparation of Lorcaserin or a pharmaceutically acceptable salt comprising the step of deprotecting N- trifluoroacetyl-8-chloro- 1 -methyl-2,3 ,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt to form Lorcaserin or a pharmaceutically acceptable salt.
  • US 8,168,624 disclose crystalline forms of Lorcaserin hydrochloride, namely three crystalline forms of Lorcaserin hydrochloride, individually designated as Form I, Form II and Form III (hemihydrate) of Lorcaserin hydrochloride.
  • Form I and Form II of Lorcaserin hydrochloride are anhydrous, hygroscopic forms, both of which readily convert to Form III (hemihydrate) of Lorcaserin hydrochloride of Formula (la), upon exposure to moisture.
  • US '624 also discloses a process for the preparation of Lorcaserin hydrochloride hemihydrate of Formula (la) which comprises mixing Lorcaserin hydrochloride of Formula (I) with a crystallizing solvent containing water and inducing precipitation of the Lorcaserin hydrochloride hemihydrate of Formula (la) from the crystallizing solvent.
  • US 2013/0158013 discloses a crystalline Form IV of Lorcaserin hydrochloride, is an anhydrous polymorph. Further US '013 disclose that Lorcaserin hydrochloride crystalline Form IV is the most stable of anhydrous polymorphs at ambient temperature.
  • US '013 also disclose a process for the preparation of Lorcaserin hydrochloride hemihydrate (Form III), comprising slurrying a first mixture comprising Lorcaserin hydrochloride salt Form IV and a first solvent to form (R) -Lorcaserin HCl hemihydrate (Form III).
  • the present invention directed towards a process for the preparation of crystalline Lorcaserin hydrochloride hemihydrate of Formula (la) with high purity and high yield,
  • the main objective of the present invention is to provide a simple and cost-effective process for the preparation of crystalline Lorcaserin hydrochloride hemihydrate of Formula (la) with high purity and good yield on commercial scale.
  • the present invention provides a process for the preparation of crystalline Lorcaserin hydrochloride hemihydrate of Formula (la), which comprises,
  • solvent used in step-(i) comprises from ester, halogenated hydrocarbon, ketone, aromatic hydrocarbon or mixture thereof.
  • ester comprises from ethyl acetate, n- propyl acetate, n-butyi acetate, isobutyl acetate, t-butyl acetate, methyl acetate or mixtures thereof;
  • halogenated hydrocarbon comprises from dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride, or mixtures thereof;
  • ketone comprises from acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methyl-pentane-2-one or mixtures thereof;
  • aromatic hydrocarbon comprises from toluene, m-xylene, o-xylene, p- xylene or mixtures thereof.
  • the process of removing water in step- (ii) from the reaction mixture preferably comprises azeotropic distillation.
  • hydrogen chloride gas is passed into the reaction mass or hydrogen chloride in an anhydrous solvent comprises ester or alcohol or mixtures thereof is added to the reaction mass to produce Lorcaserin hydrochloride (I),
  • ester comprises from ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, methyl acetate or mixtures thereof; alcohol comprises from methanol, ethanol, ethylene glycol, 1-propanol, 2- propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol or mixtures thereof.
  • anti-solvent used in step-(iv) comprises from cyclohexane, pentane, hexane, toluene, cycloheptane, methyl cyclohexane, heptane, or mixture thereof.
  • the mixture containing the crystallizing solvent and Lorcaserin hydrochloride is maintained at a temperature of about 40 to about 80, about 50 to about 70, or about 60°C prior to inducing precipitation for a period of about 1 to 24 hours.
  • Lorcaserin hydrochloride is dissolved in the crystallizing solvent prior to inducing precipitation.
  • the dissolution can be achieved by heating the mixture to a suitable temperature such as between about 40 and about 80° C.
  • precipitation of the Lorcaserin hydrochloride heminydrate product can be induced by adding anti solvent, in some embodiments, the mixture is cooled to a temperature of about - 15 to about 15° C. In some embodiments, the mixture is cooled to a temperature of about - 5 to about 10° C. In further embodiments, the mixture is cooled to a temperature of about 0 to about 5° C.
  • crystalline Lorcaserin hydrochloride hemihydrate of Formula (la) is isolated by conventional techniques such as filtration and dried the product,
  • the present invention provides a compound which is Lorcaserin hydrochloride hemihydrate (la) gains less than about 1.0%, less than about 0.5% or less than about 0.2% weight after undergoing a dynamic vapor sorption cycle.
  • Lorcaserin hydrochloride hemihydrate (Form III) shows that it is substantially non-hygroscopic, adsorbing less than 0.5 wt % water at 90% RH and the XRPD pattern showed no change in crystalline form after the dynamic vapor sorption.
  • Lorcaserin base which is used as starting material in the present invention can be prepared for example by the procedure disclosed in US 8,367,657.
  • Example-1 Process for the preparation of crystalline Lorcaserin hydrochloride hemihydrate:
  • Lorcaserin hemitartrate monohydrate salt 100 g was suspended in ethyl acetate (300 mL) and DM water (300mL) at 20-30°C. The above suspension was cooled to 10-15°C. 40% w/w Sodium hydroxide solution (38.13 g) was slowly added for about 30 mins to the reaction mixture at 10-15°C and stirred for 30 minutes. The reaction mass temperature was raised to 20-25°C. Organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL). Combined the organic layer and the organic layer was washed with 20% aqueous sodium chloride (400 mL). The solvent from the organic layer was evaporated under reduced pressure at below 40°C to afford oily material.
  • the oily material is dissolved in ethyl acetate (100 mL) at 20-30°C.
  • the reaction mass was cooled to 0-5°C.
  • Ethyl acetate-hydrogen chloride (15% w/w, 101.21 g) was slowly added for about 30 mins to the reaction mixture at 0-5°C.
  • n-heptane 400 mL was slowly added for about 30 mins at 0-5°C and stirred for 3 hours at same temperature.
  • the reaction mass was filtered and washed with pre-cooled n-heptane (100 mL). The obtained solid was dried at 30-40°C under reduced pressure to afford 75 g of the title compound.
  • Lorcaserin hemitartrate monohydrate salt 100 g was suspended in ethyl acetate (200 mL) and DM water (200mL) at 20-30°C. The above suspension was cooled to 10-15°C. 40% w/w Sodium hydroxide solution (38.13 g) was slowly added for about 30 mins to the reaction mixture at 10-15°C and stirred for 30 minutes. The reaction mass temperature was raised to 20-25°C. Organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL). Combined the organic layer and the organic layer was washed with 20% aqueous sodium chloride (400 mL). The solvent from the organic layer was evaporated under reduced pressure at below 40°C to afford oily material.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de chlorhydrate hémihydrate de lorcasérine cristalline de Formule (la), qui comprend, Formule (la) (i) la préparation d'une solution de lorcasérine-base dans un solvant ; (ii) si de l'eau est présente, l'élimination de l'eau du mélange réactionnel ; (iii) l'ajout de chlorure d'hydrogène au mélange réactionnel ; (iv) la combinaison du mélange réactionnel avec un anti-solvant approprié ; et (v) l'isolement du chlorhydrate hémihydrate de lorcasérine cristalline de Formule (la).
PCT/IB2016/051535 2015-03-24 2016-03-18 Procédé de préparation de chlorhydrate de lorcasérine WO2016151451A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP16767827.5A EP3273967A4 (fr) 2015-03-24 2016-03-18 Procédé de préparation de chlorhydrate de lorcasérine
US15/741,722 US10308611B2 (en) 2015-03-24 2016-03-18 Process for the preparation of Lorcaserin hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1487/CHE/2015 2015-03-24
IN1487CH2015 2015-03-24

Publications (1)

Publication Number Publication Date
WO2016151451A1 true WO2016151451A1 (fr) 2016-09-29

Family

ID=56979154

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/051535 WO2016151451A1 (fr) 2015-03-24 2016-03-18 Procédé de préparation de chlorhydrate de lorcasérine

Country Status (3)

Country Link
US (1) US10308611B2 (fr)
EP (1) EP3273967A4 (fr)
WO (1) WO2016151451A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478506A (zh) * 2016-09-30 2017-03-08 山东科兴生物制品有限公司 半水绿卡色林盐酸盐的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007120517A2 (fr) * 2006-04-03 2007-10-25 Arena Pharmaceuticals, Inc. Procédés de préparation de 8-chloro-1-méthyl-2,3,4,5-tétrahydro-1h-3-benzazépine et produits intermédiaires associés
WO2012030927A2 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes galéniques à libération modifiée d'agonistes de 5-ht2c, utiles pour la gestion du poids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103601645B (zh) * 2013-11-07 2016-05-25 上海适济生物科技有限公司 1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007120517A2 (fr) * 2006-04-03 2007-10-25 Arena Pharmaceuticals, Inc. Procédés de préparation de 8-chloro-1-méthyl-2,3,4,5-tétrahydro-1h-3-benzazépine et produits intermédiaires associés
US8168782B2 (en) * 2006-04-03 2012-05-01 Arena Pharmaceuticals, Inc. Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
WO2012030927A2 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes galéniques à libération modifiée d'agonistes de 5-ht2c, utiles pour la gestion du poids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3273967A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478506A (zh) * 2016-09-30 2017-03-08 山东科兴生物制品有限公司 半水绿卡色林盐酸盐的制备方法
CN106478506B (zh) * 2016-09-30 2019-03-15 山东科兴生物制品有限公司 半水绿卡色林盐酸盐的制备方法

Also Published As

Publication number Publication date
US20180194734A1 (en) 2018-07-12
US10308611B2 (en) 2019-06-04
EP3273967A1 (fr) 2018-01-31
EP3273967A4 (fr) 2018-09-12

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